Synthesis of multivalent peptidoglycan mimics and multifunctional gold nanoparticles
Miller, Douglas Wayne
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Multivalency has been shown to have a significant role in the recognition and binding of carbohydrates by proteins as well as in several biological events. The recognition of Gram-(+) bacteria by macrophage cells during an infection has been suggested to occur through the binding of a multivalent presentation of the bacterial peptidoglycan by cellular receptors on the surface of the macrophage cells and that this binding event leads to the production of TNF-± and other cytokines. While numerous studies have investigated the ability of peptidoglycan to stimulate cytokine production using cell wall preparations obtained from whole bacteria, the chemical diversity of peptidoglycan among different bacterial species as well as the inability to obtain a homogeneous preparation of peptidoglycan has led investigators to question which components of peptidoglycan are recognized by macrophage cells and whether a multivalent presentation of these structures is required for the stimulation of cytokine production. The work presented herein describes the synthesis of several peptidoglycan substructures via solid phase peptide synthesis and their subsequent conjugation to multivalent poly(ethylene glycol) scaffolds to produce homogeneous mimics of bacterial peptidoglycan. These glycoconjugates were then investigated for their ability to induce TNF-± production in order to determine which components of the peptidoglycan structure are recognized by macrophage cells. Gold nanoparticles have also been recently utilized as a novel structure for multivalent interactions. Despite recent advances in nanoparticle synthesis, the ability to produce multifunctional particles remains a challenging task with little control over the incorporation of ligands onto the particle surface. The research reported herein also describes the development of a new methodology for synthesizing multifunctional gold nanoparticles utilizing a bifunctional lysine derivative to incorporate ligands onto the particle surface with more control and selectivity.